PROJECT SUMMARY Mitochondria are organelles in cells that generate power to drive cellular metabolism. It has been reported that mitochondrial abnormality ? such as defects in mitochondrial morphology, and transport ? is prevalent in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Mutations in the gene encoding a mitochondrial protein CHCHD10 have been identified as a genetic cause of diseases including frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and related diseases. Although more than 25 genes have been identified as genetic causes of FTD and ALS, CHCHD10 is unique in that it primarily localizes in mitochondria. This suggests that CHCHD10 is essential to determine whether the degenerative changes associated with FTD and ALS are primarily dependent on abnormal mitochondrial function. Our long- term goal is to understand the mitochondrial pathogenesis associated with FTD and ALS to eventually identify molecular targets for therapeutic intervention. To investigate the function of CHCHD10 and influence on the development of FTD and ALS, we generated fruit fly (Drosophila) models for disease-causing mutations in CHCHD10. Through characterization of the models, we found out that mutant CHCHD10 proteins tend to become protein aggregates in mitochondria and generate toxicity by activating the mitochondrial quality control system. Therefore, we hypothesize that mutations on CHCHD10 increase the aggregation propensity of CHCHD10, which results in aggregate formation, activation of the PINK1-dependent pathways, and subsequent degeneration in FTD and ALS. To test this hypothesis and define pathogenic mitochondrial pathways, we propose three specific aims: (Aim 1) To investigate the role of an intrinsically disordered region of CHCHD10 on aggregation; (Aim 2) To determine a molecular mechanism of PINK1 accumulation by CHCHD10 mutants; (Aim 3) Molecular and genetic dissection of mitochondrial pathways regulated by CHCHD10. At the completion of these aims, this project will provide insights into how to control the mitochondrial pathogenesis in CHCHD10-mediated FTDALS2 as well as other FTD and ALS subtypes.